1. Field of the Invention
The present invention relates to androgen derivatives and their use in therapy.
2. Related Art
Testosterone, an anabolic androgenic C19 steroid with a hydroxy group in position 17, is the principal male sex hormone. It is either synthesised from cholesterol and secreted by the Leydig cells in the testes or formed in the adrenal cortex [Ganong, Chapter 23 in Review of Medical Physiology, (1979), pp. 336-339]. Testosterone is found in androgen dependent target tissues, such as the testes, kidneys, skin, liver and prostate, where it is converted to 5xcex1-dihydrotestosterone (DHT) by 5xcex1-reductase. DHT is required for male sexual differentiation. Testosterone is also found in the brain where it is converted to oestradiol by aromatase. This conversion permits mediation of androgenic effects which include gonadotropin secretion regulation, sexual function and protein synthesis [Handelsman, xe2x80x9cTestosterone and Other Androgens: Physiology, Pharmacology, and Therapeutic Use,xe2x80x9d in Endocrinologyxe2x80x94Volume 3, Ed""s DeGroot et al., (1995), pp. 2351-2361].
Testosterone is also found in skeletal muscle. However, testosterone is not converted to DHT in skeletal muscle tissue, due to low 5xcex1-reductase activity (Handelsman, supra). According to Catlin, anabolic androgenic steroids, such as testosterone, increase the width and cross-sectional area of muscle fibres by increasing the myofilament and myofibre number [Catlin, xe2x80x9cAnabolic Steroids,xe2x80x9d in Endocrinologyxe2x80x94Volume 3, Ed""s DeGroot el al. (1995), pp. 2362-2376]. In hypogonadal men, this results in an increase in lean body mass and body weight, and a decrease in body fat [Handelsman, xe2x80x9cTestosterone and Other Androgens: Physiology, Pharmacology, and Therapeutic Use,xe2x80x9d in Endocrinologyxe2x80x94Volume 3, Ed""s DeGroot et al. (1995), pp. 2351-2361; Catlin, xe2x80x9cAnabolic Steroids,xe2x80x9d in Endocrinologyxe2x80x94Volume 3, Ed""s DeGroot et al. (1995), pp. 2362-2376].
Testosterone and related synthetic androgens are often used in androgen replacement therapy to obtain pharmacological androgenic effects to treat conditions such as hypogonadism. Hypogonadism may be caused by a testosterone deficiency, resulting in manifestations of androgen deficiency, such as ambiguous genitalia, sexual dysfunction, osteoporosis, flushing, delayed puberty, microphallus, anaemia, incidental biochemical diagnosis or excessive fatigability [Handelsman, xe2x80x9cTestosterone and Other Androgens: Physiology, Pharmacology, and Therapeutic Use,xe2x80x9d in Endocrinologyxe2x80x94Volume 3, Ed""s DeGroot et al. (1995), pp. 2351-2361]. Androgen replacement therapy has also been used to treat muscular diseases. However, such treatment generally involves administering orally active 17xcex1-alkylated androgens which are hepatotoxic [Handelsman, xe2x80x9cTestosterone and Other Androgens: Physiology, Pharmacology, and Therapeutic Use,xe2x80x9d in Endocrinologyxe2x80x94Volume 3, Ed""s DeGroot et al. (1995), pp. 2351-2361].
In hypogonadism treatment, androgen replacement therapy often consists of administering testosterone compounds to an individual to maintain testosterone levels for a prolonged period. Testosterone is ineffective, when orally administered, due to poor intestinal absorption and rapid hepatic metabolism [Daggett et al., Hormone Res. 9:121-129 (1978)]. Therefore, the effects of testosterone must be obtained by alternative means including administering sublingual methyl testosterone, injecting testosterone or testosterone esters, implanting testosterone, administering oral testosterone derivatives, e.g., fluoxymesterone, or applying testosterone by transdermal means [Bals-Pratsch et al., Acta Endocrinologica (Copenh), 118:7-13 (1988)]. The latter method requires large patches which can be irritating or uncomfortable when applied to the scrotum. In addition, patch application can be inconvenient and is only effective when detailed instructions are followed.
Oral testosterone derivatives include 17xcex2-esters, 7xcex1-methyl, 17xcex1-alkyl or methyl, 19-normethyl and D-homoandrogens [Handelsman, xe2x80x9cTestosterone and Other Androgens: Physiology, Pharmacology, and Therapeutic Use,xe2x80x9d in Endocrinologyxe2x80x94Volume 3, Ed""s DeGroot el al. (1995), pp. 2351-2361]. Other known testosterone derivatives include testosterone substituted at the C1 position with methyl, e.g., methenolone and mesterolone. However, these compounds have reduced oral potency. Compounds with substitutions in, and additions to, the A ring, e.g., oxandrolone and stanozolol, are also known (Catlin, supra).
Testosterone has also been used in combination with a progestogen to achieve reversible male contraception [Wu et al., Journal of Clinical Endocrinology and Metabolism 84(1): 112-122 (January 1999)].
U.S. Pat. No. 5,612,317 discloses methods of treating and preventing osteoporosis and alleviating the symptoms of menopause by administering an oestrogen glycoside or oestrogen orthoester glycoside. The compounds have the formula (I): 
wherein R1 and R2 are independently hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R1 or R2 is an orthoester glycoside moiety of the Formula (II): 
wherein A represents a glycofuranosyl or glycopyranosyl ring;
R3 is hydrogen; lower C1-4 alkyl; C7-10 aralkyl; phenyl or phenyl substituted by chloro, fluoro, bromo, iodo, lower C1-4 alkyl or lower C1-4 alkoxy; or naphthyl; and
R4 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue;
with the further proviso that at least one of R1 and R2 is either a glycosidic residue or an orthoester glycoside moiety.
Hirotani and Furuya disclose the biotransformation by cultured tobacco cells of the C-19 steroid testosterone into a variety of steroid glucosides, one of which is testosterone-17-glucoside [Hirotani and Furuya, Phytochemistry 13: 2135-2142 (1974)].
Kocovský et al. disclose the synthesis of a variety of steroid glucosides including testosterone-17-glucoside and testosterone-17-glucoside tetraacetate [Kocovský et al., Coll. Czech. Chem. Commun. 38:3273-3278 (1978)].
Becker and Galili disclose the synthesis of testosterone-17-glucoside [Becker and Galili, Tetrahedron Lett. 33:4775-4778 (1992)].
Vojtxc3xad{haeck over (s)}kovxc3xa1 et al. disclose a study on the biological activity of testosterone-17-glucoside in mice [Vojtxc3xad{haeck over (s)}kovxc3xa1 et al., Int. J. Immunopharmac. 4: 469-474 (1982)]. This glucoside showed very little activity in vivo, and certainly less than testosterone administered by the same route.
It has now, surprisingly, been found that androgen glycosides taken orally are less susceptible to hepatic degradation than the corresponding unglycosylated androgen and are only substantially de-glycosylated after the first passage through the liver, thereby resulting in higher circulatory levels of the androgen. These compounds also appear to be more susceptible to gastric uptake.
The invention relates to an androgen glycoside that is not testosterone-17-xcex2-1xe2x80x2-xcex2xe2x80x2-D-glucopyranose.
The invention further relates to a compound having the Formula (III): 
wherein the dotted line represents a single or double bond;
the rings P and Q are, independently, saturated or partially unsaturated;
R is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R is an orthoester glycoside moiety of the Formula (IV): 
wherein the semi-dotted ring indicated at xe2x80x9cCxe2x80x9d is a glycofuranosyl or glycopyranosyl ring;
R8 is hydrogen; C1-4 alkyl; C7-10 aralkyl; phenyl; phenyl substituted by chloro, fluoro, bromo, iodo, C1-4 alkyl or C1-4 alkoxy; or is naphthyl;
R9 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycoside units;
R1 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkanoyl or R1 and R, together with the atoms to which they are attached, form a carbonyl group;
R2 is hydrogen or C1-4 alkyl;
R3 is hydrogen or hydroxy;
R4, where present, is hydrogen or a halogen atom;
R5, where present, is hydrogen or C1-4 alkyl;
R6 is hydrogen or C1-4 alkyl;
R14 is hydrogen or C1-4 alkyl;
A is oxygen, xe2x95x90CH,  greater than Cxe2x95x90CHOH, or is the group  greater than CHR13, wherein R13 is hydrogen or a C1-4 alkyl group, or A and B together form an optionally substituted pyrazole or isoxazole ring;
B is a carbonyl group, xe2x95x90CH,  greater than CH2 greater than CHOR7 or xe2x95x90C(OR7)xe2x80x94, wherein R7 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycoside units, or R7 is an orthoester glycoside moiety of the Formula (V): 
wherein the semi-dotted ring indicated at xe2x80x9cDxe2x80x9d represents a glycofuranosyl or glycopyranosyl ring;
R10 is hydrogen; C1-4 alkyl; C7-10 aralkyl; phenyl; phenyl substituted by chloro, fluoro, bromo, iodo, C1-4 alkyl or C1-4 alkoxy; or is naphthyl; and
R11 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycoside units; and
esters thereof.
The present invention also relates to a method for treating androgen deficiency in an animal in need thereof, a method for treating hypogonadism and related conditions such as osteoporosis, sexual dysfunction and weight loss in an animal in need thereof, a method for increasing muscle mass in an animal in need thereof, a method for the treatment of a debilitating disease in an animal in need thereof and to a method of inhibiting conception in a male animal in need thereof, comprising administering to the animal an effective amount of a compound having the Formula (III): 
wherein the dotted line represents a single or double bond;
the rings P and Q are, independently, saturated or partially unsaturated;
R is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R is an orthoester glycoside moiety of the Formula (IV): 
wherein the semi-dotted ring indicated at xe2x80x9cCxe2x80x9d is a glycofuranosyl or glycopyranosyl ring;
R8 is hydrogen; C1-4 alkyl; C7-10 aralkyl; phenyl; phenyl substituted by chloro, fluoro, bromo, iodo, C1-4 alkyl or C1-4 alkoxy; or is naphthyl;
R9 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycoside units;
R1 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkanoyl or R1 and R, together with the atoms to which they are attached, form a carbonyl group
R2 is hydrogen or C1-4 alkyl;
R3 is hydrogen or hydroxy;
R4, where present, is hydrogen or a halogen atom;
R5, where present, is hydrogen or C1-4 alkyl;
R6 is hydrogen or C1-4 alkyl;
R14 is hydrogen or C1-4 alkyl;
A is oxygen, xe2x95x90CH,  greater than Cxe2x95x90CHOH, or is the group  greater than CHR13, wherein R13 is hydrogen or a C1-4 alkyl group, or A and B together form an optionally substituted pyrazole or isoxazole ring;
B is a carbonyl group, xe2x95x90CH,  greater than CH2 greater than CHOR7 or xe2x95x90C(OR7)xe2x80x94, wherein R7 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycoside units, or R7 is an orthoester glycoside moiety of the Formula (V): 
wherein the semi-dotted ring indicated at xe2x80x9cDxe2x80x9d represents a glycofuranosyl or glycopyranosyl ring;
R10 is hydrogen; C1-4 alkyl; C7-10 aralkyl; phenyl; phenyl substituted by chloro, fluoro, bromo, iodo, C1-4 alkyl or C1-4 alkoxy; or is naphthyl; and
R11 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycoside units; and
esters thereof.
The invention also relates to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.